Human immunodeficiency virus (HIV) is the etiologic agent of acquired immunodeficiency syndrome (AIDS). HIV infection leads to depletion of CD4+ T lymphocytes. AIDS is characterized by various pathological conditions, including immune incompetence, opportunistic infections, neurological dysfunctions, and neoplastic growth.
Several drugs have been approved for treatment of this devastating disease, including azidovudine (AZT), didanosine (dideoxyinosine, ddO), d4T, zalcitabine (dideoxycytosine, ddC), nevirapine, lamivudine (epivir, 3TC), saquinavir (Invirase), ritonavir (Norvir), indinavir (Crixivan), and delavirdine (Rescriptor). However, none of the available drugs used to combat HIV is completely effective, and treatment frequently gives rise to drug-resistant virus. Thus, the search for new anti-HIV drugs continues.
HIV is a member of the lentivirus family of retroviruses. Among the viral proteins is group specific antigen (Gag). Gag associates with the plasma membrane, where viral assembly takes place.
Cyclophilin A (CyPA) is a cellular protein having immunmodulatory activity, is believed to be incorporated into HIV virions by binding to the HIV Gag protein p24CA (p24 capsid protein), and is thought to be required for productive viral infection. The Gag-CyPA complex contained in the core of the virion is surrounded by a lipid envelope bearing HIV envelope glycoproteins. Cyclophilin A (CyPA) is a cis/trans peptidyl prolyl isomerase that has been shown to bind to the immunosuppressive drug cyclosporinA (CsA). Immunosuppression by CsA is thought to result when the cyclophilin-cyclosporin complex binds and inhibits calcinuerin, a calcium-dependent, serine-threonine phosphatase required for transcriptional activation of many cytokine genes in stimulated T cells. The CsA binding site on CyPA is separate and distinct from the portion of CyPA that has peptidyl-prolyl cis/trans isomerase (PPlase) activity and the action of CsA on CyPA does not depend on the PPIase activity. In addition, neither the immunosuppressive activity nor the reported anti-viral activity of CsA depend on the PPIase activity of CyPA.
The therapeutic anti-viral potential of intervention at the level of the CyPA-p24CA interaction has been investigated. However, drug treatments that target the CyPA-p24CA interaction suffer from certain drawbacks, including the following. The treatments are limited to HIV-1 because CyPA is present only in HIV1 but not in HIV-2 virions. The treatments do not effect a complete block of release of virions. The treatment only intervenes at the stage of viral infection, i.e., viral entry into a cell. Once a cell is infected, treatments targeted to inhibiting the CyPA-p24CA interaction are completely ineffective, as such treatments do not reduce viral replication. The CyPA-p24CA interaction does not require the PPIase activity of CyPA; instead, this interaction is limited to the binding of CyPA to Gag.
Another HIV protein, Viral protein R (Vpr; also called “lentiviral R protein” as it is common to all known primate lentiviruses, including HIV-1, HIV-2 and SIV), is a 96-amino acid, 14 kD protein that performs two distinct functions during HIV replication. Vpr is incorporated into the HIV virion and helps to target the viral preintegration complex (PIC) to the nucleus in nondividing cells through its nuclear localization signal. An interaction between Vpr and the p6 portion of the Gag protein is believed to responsible for the packaging of Vpr into the virion. Vpr is also responsible for arresting HIV infected cells in the G2 phase of the cell cycle, which results in increased virus production. The mechanism of G2 cell cycle arrest is unknown, but Vpr expression has been correlated with a decrease in p34cdc2/cyclin B complex activity.
Despite the availability of a number of drugs to combat HIV infections, there is a need in the art for additional drugs that inhibit HIV replication, and which are suitable for treating HIV and other lentiviral infections.
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